Hypoxia-Induced VISTA Promotes the Suppressive Function of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment
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Abstract
Tumor hypoxia is a negative prognostic factor that is implicated in oncogenic signal activation, immune escape, and resistance to treatment. Identifying the mechanistic role of hypoxia in immune escape and resistance to immune-checkpoint inhibitors may aid the identification of therapeutic targets. We and others have shown that V-domain Ig suppressor of T-cell activation (VISTA), a negative checkpoint regulator in the B7 family, is highly expressed in the tumor microenvironment in tumor models and primary human cancers. In this study, we show that VISTA and HIF1α activity are correlated in a cohort of colorectal cancer patients. High VISTA expression was associated with worse overall survival. We used the CT26 colon cancer model to investigate the regulation of VISTA by hypoxia. Compared with less hypoxic tumor regions or draining lymph nodes, regions of profound hypoxia in the tumor microenvironment were associated with increased VISTA expression on tumor-infiltrating myeloid-derived suppressor cells (MDSC). Using chromatin immunoprecipitation and genetic silencing, we show that hypoxia-inducible factor (HIF)-1α binding to a conserved hypoxia response element in the VISTA promoter upregulated VISTA on myeloid cells. Further, antibody targeting or genetic ablation of VISTA under hypoxia relieved MDSC-mediated T-cell suppression, revealing VISTA as a mediator of MDSC function. Collectively, these data suggest that targeting VISTA may mitigate the deleterious effects of hypoxia on antitumor immunity.
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Hypoxia upregulates the expression of PD-L1 in malignant and immune regulatory cells.
“Hypoxia also upregulates the expression of programmed cell death ligand 1 (PD-L1) in malignant and immune regulatory cells.”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [18]
Hypoxia upregulates expression of immune checkpoint molecules, such as VISTA and PD-L1, on MDSCs, promoting their immunosuppressive phenotype.
“In addition, hypoxia upregulates expression of immune checkpoint molecules, such as VISTA and programmed cell death ligand 1 (PD-L1), on myeloid-derived suppressor cells (MDSCs), promoting their immunosuppressive phenotype (17, 18).”
From Cross-talk between HIF and PD-1/PD-L1 pathways in carcinogenesis and therapy (2022) · cites this paper as [18]
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- Authors
- Deng, J., Li, J., Sarde, A., Lines, J. L., Lee, Y.-C., Qian, D. C., Pechenick, D. A., Manivanh, R., Le Mercier, I., Lowrey, C. H., Varn, F. S., Cheng, C., Leib, D. A., Noelle, R. J., & Mabaera, R.
- Affiliations
- Dartmouth College (US)
- 1Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
- ImmuNext (United States) (US)
- Dartmouth–Hitchcock Medical Center (US)
- Corresponding author
- Mabaera, Rodwell
- ORCID
- Venue
- Cancer Immunology Research
- Published
- 2019-07-01
- Volume
- 7
- Issue
- 7
- Pages
- 1079-1090
- ISSN
- 2326-6066 (ISSN-L)
- 2326-6074
- PMC
- PMC6606337
- OpenAlex
- W2946242397
- Cited by
- 224
- References
- 42
- Citations by year
- 2026: 27 · 2025: 28 · 2024: 42 · 2023: 30 · 2022: 33 · 2021: 37 · 2020: 23 · 2019: 3
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Immunology Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (1R01AI098007)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- VISTA, tumor hypoxia, myeloid-derived suppressor cells, HIF-1α, colorectal cancer, tumor microenvironment, immune checkpoint, T cell suppression, hypoxia response element, antitumor immunity, immune evasion, overall survival
- MeSH terms
- Myeloid-Derived Suppressor Cells, Adenocarcinoma, Animals, Hypoxia, Female, Humans, Lymphocyte Activation, Mice, Inbred BALB C, Prognosis, T-Lymphocytes, Tumor Cells, Cultured, Colorectal Neoplasms, Cohort Studies, Survival Rate, Case-Control Studies, Apoptosis, Cell Proliferation, T-Lymphocytes, Regulatory, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Tumor Microenvironment, B7 Antigens
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